The response of T lymphocytes to disease states, such as infection and chronic diseases like cancer, is complicated and involves intercellular interactions and the production of soluble mediators (called cytokines or lymphokines). Activation of T cells normally depends on an antigen-specific signal following contact of the T cell receptor (TCR) with an antigenic peptide presented via the major histocompatibility complex (MHC) while the extent of this reaction is controlled by positive and negative antigen-independent signals eminating from a variety of co-stimulatory molecules. The latter are commonly members of the CD28/B7 family. Conversely, Programmed Death-1 (PD-1) is a member of the CD28 family of receptors that delivers a negative immune response when induced on T cells. Contact between PD-1 and one of its ligands (B7-H1 or B7-DC) induces an inhibitory response that decreases T cell multiplication and/or the strength and/or duration of a T cell response.
Thus, the T lymphocyte response is regulated by various factors, including cell surface molecules that act as receptors, where the latter include both the TCR complex as well as other surface molecules.
In sum, an antigen specific T cell response is mediated by two signals: 1) engagement of the TCR with antigenic peptide presented in the context of HC (signal 1), and 2) a second antigen-independent signal delivered by contact between different receptor/ligand pairs (signal 2). This “second signal” is critical in determining the type of T cell response (activation vs tolerance) as well as the strength and duration of that response, and is regulated by both positive and negative signals from costimulatory molecules, such as the B7 family of proteins.
The most extensively characterized T cell costimulatory pathway is B7-CD28, in which B7-1 (CD80) and B7-2 (CD86) each can engage the stimulatory CD28 receptor and the inhibitory CTLA-4 (CD152) receptor. In conjunction with signaling through the T cell receptor, CD28 ligation increases antigen-specific proliferation of T cells, enhances production of cytokines, stimulates differentiation and effector function, and promotes survival of T cells (Lenshow, et al., Annu. Rev. Immunol., 14:233-258 (1996); Chambers and Allison, Curr. Opin. Immunol., 9:396-404 (1997); and Rathmell and Thompson, Annu. Rev. Immunol., 17:781-828 (1999)). In contrast, signaling through CTLA-4 is thought to deliver a negative signal that inhibits T cell proliferation, IL-2 production, and cell cycle progression (Krummel and Allison, J. Exp. Med., 183:2533-2540 (1996); and Walunas, et al., J. Exp. Med., 183:2541-2550 (1996)). Other members of the B7 family of costimulatory molecules include B7-H1 (Dong, et al, Nature Med., 5:1365-1369 (1999); and Freeman, et al., J. Exp. Med., 192:1-9 (2000)), B7-DC (Tseng, et al., J. Exp. Med., 193:839-846 (2001); and Latchman, et al., Nature Immunol., 2:261-268 (2001)), B7-H2 (Wang, et al., Blood, 96:2808-2813 (2000); Swallow, et al., Immunity, 11:423-432 (1999); and Yoshinaga, et al., Nature, 402:827-832 (1999)), B7-H3 (Chapoval, et al., Nature Immunol., 2:269-274 (2001)) and B7-H4 (Choi, et al., J. Immunol., 171:4650-4654 (2003); Sica, et al., Immunity, 18:849-861 (2003); Prasad, et al., Immunity, 18:863-873 (2003); and Zang, et al., Proc. Natl. Acad. Sci. U.S.A., 100:10388-10392 (2003)). B7-H5 (described in WO 2006/012232) is a newly discovered member of the B7 family.
B7 family molecules have a membrane proximal IgC (constant) domain and a membrane distal IgV (variable) domain. The CD28-like family of receptors for these ligands share a common extracellular IgV-like domain. Interactions of receptor-ligand pairs are mediated predominantly through residues in the IgV domains of the ligands and receptors (Schwartz, et al., Nature Immunol., 3:427-434 (2002)). In general, IgV domains are described as having two sheets that each contains a layer of β-strands (Williams and Barclay, Annu. Rev. Immunol., 6:381-405 (1988)). The front and back sheets of CTLA-4 contain strands A′GFC′C and ABEDC, respectively (Ostrov, et al., Science, 290:816-819 (2000)), whereas the front and back sheets of the B7 IgV domains are composed of strands AGFCC′C″ and BED, respectively (Schwartz, et al., Nature, 410:604-608 (2001); Stamper, et al., Nature, 410:608-611 (2001); and Ikemizu, et al., Immunity, 12:51-60 (2000)). Crystallographic analysis revealed that the CTLA-4/B7 binding interface is dominated by the interaction of the CDR3-analogous loop from CTLA-4, composed of a MYPPPY motif, with a surface on B7 formed predominately by the G, F, C, C′ and C″ strands (Schwartz, et al., Nature, 410:604-608 (2001); and Stamper, et al., Nature, 410:608-611 (2001)). Data from amino acid homologies, mutation, and computer modeling provide support for the concept that this motif also is a major B7-binding site for CD28 (Bajorath, et al., J. Mol. Graph. Model., 15:135-139 (1997)). Although the MYPPPY motif is not conserved in ICOS, the receptor for B7-H2, studies have indicated that a related motif having the sequence FDPPPF and located at the analogous position is a major determinant for binding of ICOS to B7-H2 (Wand, et al., J. Exp. Med., 195:1033-1041 (2002)).
B7-DC (also called PD-L2 or CD273) is a relatively new member of the B7 family, and has an amino acid sequence that is about 34% identical to B7-H1 (also called PD-L1). Human and mouse B7-DC orthologues share about 70% amino acid identity. While B7-H1 and B7-DC transcripts are found in various tissues (Dong, et al., Nature Med., 5:1365-1369 (1999); Latchman, et al., Nature Immunol., 2:261-268 (2001); and Tamura, Blood, 97:1809-1816 (2001)), the expression profiles of the proteins are quite distinct. B7-H1 is broadly expressed on a wide variety of tissue and cell types, while B7-DC expression is predominantly restricted to activated dendritic cells (DC) and macrophages.
It has been shown that both B7-H1 and B7-DC bind to PD-1 (Freeman, et al., J. Exp. Med., 192:1027-1034 (2000)), a distant member of the CD28 family with an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (Ishida, et al., EMBO J., 11:3887-3895 (1992)). PD-1, a member of the CD28 family of receptors, is inducibly expressed on activated T cells, B cells, natural killer (NK) cells, monocytes, DC, and macrophages (Keir, et al Curr. Opin. Immunol. 19:309-314 (2007)).
The primary result of PD-1 ligation by its ligands is to inhibit signaling downstream of the T cell Receptor (TCR). Therefore, signal transduction via PD-1 usually provides a suppressive or inhibitory signal to the T cell that results in decreased T cell proliferation or other reduction in T cell activation. B7-H1 is the predominant PD-1 ligand causing inhibitory signal transduction in T cells. The present invention solves the problem of undesired T cell inhibition by providing agents that bind to PD-1 and thus prevent inhibitory signal transduction, or else bind to ligands of PD-1 such as B7-H1, thereby preventing the ligand from binding to PD-1 to deliver an inhibitory signal. In either case, T cell responses, such as T cell proliferation or activation, are stimulated.
B7-H1 is the predominant PD-1 ligand, likely due to its broader distribution and higher expression levels. PD-1 inhibition occurs only when PD-1 and TCR are ligated in close proximity to each other, in the context of the immune synapse. PD-1 and its ligands have been the topic of several review articles.
B7-H1 is also over expressed in many cancers (including breast cancer, colon cancer, esophageal cancer, gastric cancer, glioma, leukemia, lung cancer, melanoma, multiple myeloma, ovarian cancer, pancreatic cancer, renal cell carcinoma, and urothelial cancer), and has been linked to poor prognosis. B7-H1 is expressed by many tumor cell lines, especially following stimulation with interferon gamma (IFN-γ), and is also upregulated on tumor infiltrating myeloid derived suppressor cells (MDSC). For example, PD-1 is up-regulated on tumor specific CD8 T cells and is associated with functional impairment, anergy, exhaustion, and apoptosis. PD-1 upregulation has also been associated with dysfunctional and/or suppressive phenotypes on additional cell types, such as regulatory T cells (Treg) and natural killer T (NKT) cells.
The present invention makes use of such molecular functions by providing treatment regimens for treating diseases through increased T cell activity, especially cancer and infectious diseases.